This invention is directed to compounds of the formula I as described herein, to a pharmaceutical composition comprising such compounds and to methods of treating disorders or conditions that may be treated by administration of such compounds to a mammal in need, including humans. In particular, the compounds of the current invention are potentially useful for treating, e.g., depression, mood disorders, anxiety, schizophrenia, bipolar disorder (also referred to as manic-depressive disorder), addiction, obsessive-compulsive disorder, cognitive impairment, Parkinson's and Alzheimer's diseases.
Depression is a disease that afflicts a large segment of the U.S. population, estimated to be more than 20 million patients (Kessler, R. C., et al, Archives of General Psychiatry, 2005, 62 (6):617-27). Symptoms of depression include alteration in mood (e.g., sadness, apathy), negative self-concept (e.g., self-reproach), vegetative changes (e.g., insomnia, anorexia, loss of libido), and changes in activity level (e.g., agitation, listlessness); it may be uni-polar or bi-polar (i.e., manic-depression). Traditionally, treatment of depressed individuals has included the use of psychotherapy, natural and/or synthetic pharmacological agents, or a combination of the two. Natural agents have included substances such as St. John's Wort.
Since the 1950's, pharmacological substances have played a dominant role in the treatment and recovery of patients. Following the recognition of the role of the neurotransmitters (NT) such as serotonin (5-hydroxytryptamine, 5-HT) in the Central Nervous System (CNS), more effective drugs have been designed and marketed to regulate this mood disorder. The drugs that are currently available—and most often prescribed—for the treatment of depression include serotonin selective reuptake inhibitors (SSRI's, e.g., fluoxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (SNRI's, e.g., venlafaxine, duloxetine), tricyclic antidepressants (TCA's, e.g., desipramine, nortriptyline, amitriptyline) and other NTs in the CNS. While many of these therapeutic agents provide benefit to the patients who take them as prescribed, it may take several weeks or longer to achieve significant clinical relief from their most serious symptoms, e.g., a major concern for physicians dealing with depressed patients is the increased risk of suicide. Furthermore, it is estimated that approximately 30% or more of diagnosed patients do not achieve adequate clinical relief even after treatment with three or more different antidepressant medications. Coupled with potential side effects (e.g., gastrointestinal disturbances, sexual dysfunction and reduced libido) as well as development of potentially life-threatening serotonin syndrome, physicians and their patients are eagerly awaiting discovery of safer and more broadly efficacious treatments.
There continues to be great interest in identifying novel mechanisms of action for the treatment of depression and related mood disorders. Recently, interest has been drawn to the use of selective opioid agonists and antagonists, specifically those that interact with the kappa (κ) subtype, as a means of achieving faster onset of action with potentially better toleration (Carlezon, W. A., et al, Pharmacology & Therapeutics, 2009), (Zhang, H., et al, European Journal of Pharmacology, 2007, 570:89-96), (Todtenkopf, M. S., et al, Psychopharmacology (Berl.) 2004, Jan. 16), (Ibegbu, A. O., et al, British Journal of Pharmacology and Toxicology, 2011, 2(2):84-91) and (Gharagozlou, P., et al, BioMed Central Pharmacology (Open Access), 2006, January 25). Mague, et al (Journal of Pharmacology and Experimental Therapeutics, 2003, 305:323-330) have published results of activity in a rat forced—swim test that demonstrate the potential for antidepressant activity of kappa opioid receptor (KOR) antagonists.
A review of the role of opioid receptors in the development of mood disorders is also available (Lutz, P. -E. and Kieffer, B. L., Trends in Neurosciences, 2013, 36(3):195-206). A. T. Knoll and W. A. Carlezon (Brain Research, 2010, 1314:56-73) have also reported the results of their studies of the roles of dynorphin and KOR with respect to the role of stress in depression.
M. Bartolato, et al (Biological Psychiatry, 2005, 57:1550-1558) have claimed positive results from studies of KOR agonists in a rat model of schizophrenia—disruption of prepulse inhibition—which suggest a possible therapeutic benefit for compounds having this activity. S. Yoshikawa, et al (European Journal of Pharmacology, 2009, 606:102-108) have also described their findings with the KOR agonist TRK-820 in rat models of schizophrenia and suggest a therapeutic potential for this compound in the treatment of psychotic behavior.
Kappa receptors have also been implicated in addictive behavior and antagonists have shown potential utility in a mouse model of nicotine addiction and withdrawal (Jackson, K. J., et al, Psychopharmacology, DOI 10.1007/s00213-010-1803-1).
B. Hahn, et al, (Neuropharmacology, 2000, 39:2848-2855) have studied modulation of nicotine-induced behavior with Kappa agonists in rats. J. L Kissler, et al (Biological Psychiatry, 2013) have studied the potential utility of KOR substances in alcohol self-administration, whereas the value of KOR selective compounds for the treatment of opioid and stimulant addiction was reviewed by S. D. Glick, et al (Brain Research, 1995, 681:147-152) and E. R. Butelman, et al (Trends in Neurosciences, 2012, 35(10):587-596).
Kappa opioid receptors, interacting with the dynorphin system in the CNS, also appear to play a significant role in other psychiatric disorders, including anxiety (e.g., see Tejeda, H. A., et al, Cellular and Molecular Life Science, 2011, 69:857-896; Peters, M. F., et al, European Journal of Pharmacology, 2011, 661:27-34) and therefore KOR agonists or antagonists may offer a therapeutic value in treating anxiety disorders.
KOR antagonists have been disclosed, e.g., in U.S. Pat. No. 6,534,514 (Portoghese, P. S., et al, Issued Mar. 18, 2003), U.S. Pat. No. 6,559,159 (Carroll, F. I., et al, Issued May 6, 2003) and U.S. Pat. No. 7,709,522 (Buezo, N. D., et al, Issued May 4, 2010). Similarly, kappa agonists have been disclosed in U.S. Pat. No. 5,804,595 (Portoghese, P. S., et al, Issued Sep. 8, 1998) and U.S. Pat. No. 6,191,126 (Gamache, D. A.; Issued Feb. 20, 2001). The syntheses and receptor selectivities of novel chemotypes which exhibit potent antagonist or agonist activity at the KOR have also been described by K. J. Frankowski, et al (ACS Chemical Neuroscience, 2012, 3:221-236), C. H. Mitch, et al (Journal of Medicinal Chemistry, 2011, 54:8000-8012), T. E. Prisinzano, (Journal of Medicinal Chemistry, 2013, 56:3435-3443) and C. M. Kormos, et al, (Journal of Medicinal Chemistry, 2013, 56:4551-4567). T. A. Brugel, et al (Bioorganic and Medicinal Chemistry Letters, 2010, 20:5405-5410 and 20:5847-5852) have also disclosed a novel series of azabicyclo[3.2.1]octan-3-yloxy-benzamides with potent and selective K antagonist activity.
It has recently been reported that the biotech company Alkermes has initiated a Phase 2 study of ALKS 5461, a combination of buprenorphine (a mixed kappa opioid receptor antagonist/ mu opioid receptor agonist which has demonstrated antidepressant properties in human studies) and ALKS 33 (i.e., samidorphan), a selective mu opioid receptor antagonist that does not affect the delta- or kappa- opioid receptors) in clinical trials of patients suffering from major depressive disorder (http://en.wikipedia.org/w/index.php?title=Samidorphan&oldid =555540304).
Recently, there has also been increased awareness of the potential for compounds which function as sigma-1 receptor ligands. Such ligands have been shown to modulate NMDA and dopamine neurotransmission in animal studies, suggesting utility for treatment of psychiatric diseases including depression (Debonnel G, de Monitgny C, Life Sciences (1996) 58(9):721-734), schizophrenia and OCD (e.g., see Ishikawa M, Hashimoto K, J. Receptor, Ligand and Channel Res. (2010) 3:25-36; Cobbs E J, Entrena J M, Nieto F R, Cendan C M and del Pozo E, Current Neuropharmacology (2008) 6:344-366); Hayashi T, Su TP, CNS Drugs (2004) 18(5):269-284). Clinical improvement of cognitive symptoms in schizophrenic patients has been observed through concomitant use of sigma-1 receptor agonists like fluvoxamine and donepezil (Niitsu T, Hashimoto K, Curr. Pharm. Des., (2012) 18(7):857-883). Others have suggested a role in the treatment of Alzheimer's Disease through regulation of neurite outgrowth (Kimura Y, Fujita Y, Yamashita T, Receptors & Clinical Investigation (2014) 1:8-12).
The present invention relates to the use of novel cycloalkyl-diamines and to their pharmaceutical compositions in the treatment of psychiatric disorders from the group consisting of depression, mood disorders, anxiety, schizophrenia, bipolar disorder (also referred to as manic-depressive disorder), addiction, cognitive impairment, Parkinson's and Alzheimer's diseases in mammals, including humans. Many of the compounds disclosed in this application exhibit affinity for the kappa opioid receptor and, in some cases, demonstrate significant activity as sigma-1 ligands.